KR100515227B1 - Acid-Addition Salts of Optically Active Piperidine Compound and Process for Producing the Same - Google Patents
Acid-Addition Salts of Optically Active Piperidine Compound and Process for Producing the Same Download PDFInfo
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- KR100515227B1 KR100515227B1 KR10-1999-7005802A KR19997005802A KR100515227B1 KR 100515227 B1 KR100515227 B1 KR 100515227B1 KR 19997005802 A KR19997005802 A KR 19997005802A KR 100515227 B1 KR100515227 B1 KR 100515227B1
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Abstract
Description
본 발명은 항히스타민 활성 및 항알레르기 활성이 우수한 (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산의 벤젠술폰산염 또는 벤조산염 및 그의 제조 방법 및 그의 라세미체형 중간체로서 중요한 4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘의 광학 분할 방법에 관한 것이다. 이 산부가염은 흡습성이 적고, 물리화학적 안정성이 우수하므로, 의약품으로서 특히 적합한 화합물이다. 또한, 본 발명은 이들을 유효 성분으로 하는 의약 조성물에 관한 것이다.The present invention provides benzenesulfonate or benzoate of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid having excellent antihistamine activity and antiallergic activity, and It relates to a process for its preparation and an optical cleavage method of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine, which is important as its racemic intermediate. This acid addition salt is a particularly suitable compound as a medicine because of its low hygroscopicity and excellent physicochemical stability. Moreover, this invention relates to the pharmaceutical composition which uses these as an active ingredient.
일본 특허공개평 2-25465호 공보에 기재된 하기 화학식 Ⅱ로 표시되는 피페리딘 화합물(Ⅱ) 또는 그의 염은 종래의 항히스타민제의 경우에 종종 나타나는 중추 신경에 대한 자극 또는 억압이라는 이차적 효과가 최소한으로 억제된다는 특징을 가지고 있으며, 쐐기풀 발진, 습진, 피부염 등의 알레르기성 피부 질환, 알레르기성 비염, 감기 등의 기도염증에 의한 재채기, 콧물, 기침 및 기관지 천식의 치료, 및 처리용 의약품으로서 기대되고 있다.Piperidine compound (II) represented by the following general formula (II) or a salt thereof described in Japanese Patent Application Laid-Open No. 2-25465 has a minimal secondary effect of stimulation or repression on the central nerve, which is often found in the case of conventional antihistamines. It is characterized by being suppressed and is expected to be used as a medicine for treating allergic skin diseases such as nettle rash, eczema, dermatitis, sneezing caused by airway inflammation such as allergic rhinitis, cold, runny nose, cough and bronchial asthma. .
식 중, A는 저급 알킬기, 히드록실기, 저급 알콕시기, 아미노기, 저급 알킬아미노기, 페닐기 또는 저급 알킬 치환 페닐기를 나타낸다.In formula, A represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a phenyl group, or a lower alkyl substituted phenyl group.
이 피페리딘 화합물(Ⅱ)을 의약으로서 보다 바람직한 광학 활성체로 효율적으로 제조하기 위해서는 중간체를 광학 분할하고, 이를 원료로서 사용하는 것이 바람직하다. 그러나, 이 피페리딘 화합물(Ⅱ)은 1개의 비대칭 탄소를 가지고 있지만, 광학 활성체를 단리하는 방법은 현재까지 알려져 있지 않다.In order to efficiently manufacture this piperidine compound (II) as an optically active substance more preferable as a medicament, it is preferable that the intermediate is optically divided and used as a raw material. However, although this piperidine compound (II) has one asymmetric carbon, a method for isolating an optically active substance is not known until now.
일반적으로 광학 이성질체간에는 약리 활성 또는 안전성이 상이하고, 또한 대사 속도, 단백질 결합율에도 차이가 있다는 것이 알려져 있다[Pharmacia, 25(4), pp.311-336, 1989]. 따라서, 의약품으로 만들기 위해서는 약리학적으로 바람직한 광학 이성질체를 고광학 순도로 제공할 필요가 있다. 또한, 이 광학 이성질체의 의약품으로서의 고도한 품질을 확보하기 위하여, 물리화학적 안정성이 우수한 성질을 갖는 것이 요망된다.In general, it is known that optical isomers have different pharmacological activity or safety, and also metabolic rate and protein binding rate are different [Pharmacia, 25 (4), pp. 311-336, 1989]. Thus, in order to make a drug, it is necessary to provide pharmacologically desirable optical isomers with high optical purity. Moreover, in order to ensure the high quality of this optical isomer as a medicine, it is desired to have the property which is excellent in physicochemical stability.
본 발명자들은, 이 과제 해결을 위하여 예의 연구를 거듭한 결과, 하기 화학식 Ⅰ로 표시되는 광학 활성인 (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산의 벤젠술폰산염 및 벤조산염이 의약품으로서 바람직한 우수한 안정성을 갖는다는 것을 발견하여, 본 발명을 완성하기에 이르렀다.MEANS TO SOLVE THE PROBLEM As a result of earnestly researching in order to solve this subject, the present inventors found that optically active (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] represented by the following general formula (I). The benzenesulfonate and benzoate salts of piperidino] butanoic acid have been found to have excellent stability desirable as a medicament, thus completing the present invention.
<발명의 개시><Start of invention>
제1 발명은 하기 화학식 Ⅰ로 표시되는 절대 배치가 (S)인 광학 활성 피페리딘 화합물(Ⅰ)의 벤젠술폰산염 및 벤조산염에 관한 것이다.1st invention relates to the benzene sulfonate and benzoate of optically active piperidine compound (I) whose absolute batch represented by following formula (I) is (S).
식 중, *는 비대칭 탄소를 나타낸다.In the formula, * represents an asymmetric carbon.
제2의 발명은, 상기 화학식 Ⅰ로 표시되는 절대 배치가 (S)인 광학 활성 피페리딘 화합물을 벤젠술폰산 또는 벤조산과 염형성 반응시키는 것인, 상기 광학 활성 피페리딘 화합물의 벤젠술폰산염 및 벤조산염의 제조 방법에 관한 것이다.2nd invention is the benzene sulfonate of the said optically active piperidine compound which carries out the salt-forming reaction of the optically active piperidine compound whose absolute arrangement represented by the said Formula (I) is (S) with benzenesulfonic acid or benzoic acid, and It relates to a method for producing benzoate.
제3의 발명은, (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산·벤젠술폰산염 또는 벤조산염을 유효 성분으로 하는 의약 조성물에 관한 것이다.A third invention is a pharmaceutical comprising (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid, benzenesulfonate or benzoate as an active ingredient It relates to a composition.
나아가, 본 발명은 (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘에 하기 화학식 Ⅶ로 표시되는 광학 활성 프로피온산 화합물(Ⅶ) 또는 광학 활성 N-아실-아미노산을 작용시키고, 생성된 2종의 부분 입체 이성질체 염의 용해도 차이를 이용하여 난용성의 부분 입체 이성질체 염을 분리, 채취하고, 이어서 이 염을 분해하고, 얻어진 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘에 하기 화학식 Ⅴ로 표시되는 에스테르를 작용시켜 하기 화학식 Ⅵ으로 표시되는 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘부탄산에스테르를 얻은 후, 이것을 가수 분해하고, 이를 다시 벤젠술폰산 또는 벤조산과 염형성 반응시키는 것인, 상기 화학식 Ⅰ로 표시되는 광학 활성 피페리딘 화합물(Ⅰ)의 벤젠술폰산염 또는 벤조산염의 제조 방법에 관한 것이다.Furthermore, the present invention provides an optically active propionic acid compound (VII) or an optically active N-acyl represented by the following formula (VII) in (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine -Amino acids are reacted and the poorly soluble diastereomeric salts are separated and taken up using the solubility differences of the two resulting diastereomeric salts, followed by decomposition of this salt to obtain (S) -4-[(4 (S) -4-[(4-chlorophenyl) (2-pyri) represented by the following formula (VI) by reacting an ester represented by the following formula (V) to -chlorophenyl) (2-pyridyl) methoxy] piperidine The benzene of the optically active piperidine compound (I) represented by the above formula (I), which is obtained by obtaining dill) methoxy] piperidine butanoic acid ester, and then hydrolyzing it and salt-reacting it with benzenesulfonic acid or benzoic acid. It relates to a process for preparing sulfonate or benzoate.
식 중, R은 메틸기, 에틸기 등의 저급 알킬기를 나타내고, W는 할로겐 원자 등의 이탈기 또는 메탄술포닐옥시기, p-톨루엔술포닐옥시기 등의 반응성 에스테르기를 나타낸다.In formula, R represents lower alkyl groups, such as a methyl group and an ethyl group, W represents reactive groups, such as leaving groups, such as a halogen atom, or methanesulfonyloxy group, and p-toluenesulfonyloxy group.
<발명을 실시하기 위한 최상의 형태>Best Mode for Carrying Out the Invention
(S)-피페리딘 화합물(Ⅰ)의 벤젠술폰산염 또는 벤조산염은 하기 반응식(1)로 표시되는 방법으로 제조할 수가 있다(이하, 염형성 반응이라 함).Benzene sulfonate or benzoate of (S) -piperidine compound (I) can be manufactured by the method shown by following Reaction formula (1) (henceforth a salt formation reaction).
식 중, HX는 벤젠술폰산 또는 벤조산을 나타내며, *는 상기와 동일 의미를 갖는다.In the formula, HX represents benzenesulfonic acid or benzoic acid, and * has the same meaning as above.
염형성 반응에서는 벤젠술폰산 또는 벤조산을 (S)-피페리딘 화합물(Ⅰ) 1몰에 대하여 0.8 내지 2.5배몰, 적합하게는 0.9 내지 1.2배몰을 사용하여 행할 수가 있다.In the salt formation reaction, benzenesulfonic acid or benzoic acid can be carried out using 0.8-2.5 times mole, suitably 0.9-1.2 times mole with respect to 1 mol of (S) -piperidine compounds (I).
염형성 반응에 사용되는 용매는 반응에 관여하지 않는 용매라면 특별한 제한은 없지만, 예를 들면 아세토니트릴, 프로피오니트릴과 같은 니트릴류, 아세트산메틸, 아세트산에틸과 같은 에스테르류, 메탄올, 에탄올, 1-프로판올, 2-프로판올 등의 알코올류, 아세톤, 디메틸포름아미드 등을 들 수가 있으며, 에탄올, 2-프로판올, 아세토니트릴, 아세트산에틸이 바람직하다. 또한, 본 발명에서 사용되는 용매는 상기한 용매를 단독으로 사용하여도 좋고, 임의의 2종류 이상의 용매를 혼합하여 사용하여도 좋다.The solvent used for the salt-forming reaction is not particularly limited as long as it is a solvent that does not participate in the reaction. For example, acetonitrile, nitriles such as propionitrile, esters such as methyl acetate and ethyl acetate, methanol, ethanol and 1- Alcohols, such as propanol and 2-propanol, acetone, dimethylformamide, etc. are mentioned, Ethanol, 2-propanol, acetonitrile, ethyl acetate is preferable. In addition, the solvent used by this invention may use said solvent independently, and may mix and use arbitrary 2 or more types of solvent.
염형성 반응에 사용되는 용매의 사용량은 통상 (S)-피페리딘 화합물(Ⅰ) 1몰에 대하여 0.5 내지 30 ℓ이고, 바람직하게는 0.8 내지 20 ℓ이며, 더욱 바람직하게는 1 내지 10 ℓ이다.The amount of the solvent used for the salt formation reaction is usually 0.5 to 30 L, preferably 0.8 to 20 L, more preferably 1 to 10 L, per 1 mol of the (S) -piperidine compound (I). .
염형성 반응의 온도는 예를 들면 5 내지 50 ℃, 바람직하게는 10 내지 35 ℃이고, 염석출시의 온도는 예를 들면 -30 ℃ 내지 30 ℃, 바람직하게는 -10 ℃ 내지 15 ℃이다. 또한, 첨가 방법에는 특별한 제한은 없으나, 예를 들면 (S)-피페리딘 화합물(Ⅰ)과 용매의 혼합액에, 벤젠술폰산 또는 벤조산을 용매에 용해시켜 첨가하는 방법을 들 수가 있다.The temperature of the salt formation reaction is, for example, 5 to 50 ° C, preferably 10 to 35 ° C, and the temperature at the time of salt precipitation is, for example, -30 ° C to 30 ° C, preferably -10 ° C to 15 ° C. Moreover, there is no restriction | limiting in particular in the addition method, For example, the method of melt | dissolving and adding benzene sulfonic acid or benzoic acid to a mixed liquid of (S) -piperidine compound (I) and a solvent in a solvent is mentioned.
생성된 (S)-피페리딘 화합물(Ⅰ)의 염은 이 기술 분야의 통상법에 따라 여과, 원심 분리 등에 의해 분취한 후 적절히 세정, 건조함으로써 용이하게 얻을 수가 있다.The salt of the resulting (S) -piperidine compound (I) can be easily obtained by fractionating by filtration, centrifugal separation, or the like according to a conventional method in the art, followed by appropriate washing and drying.
이어서, 본 발명의 (S)-피페리딘 화합물(Ⅰ)의 제조 방법에 대하여 설명한다. Next, the manufacturing method of the (S) -piperidine compound (I) of this invention is demonstrated.
본 발명의 (S)-피페리딘 화합물(Ⅰ)은 하기 반응식(2)로 표시되는 방법으로 제조할 수가 있다.(S) -piperidine compound (I) of this invention can be manufactured by the method shown by following Reaction formula (2).
식 중, W는 이탈기, 예를 들면 염소 원자, 브롬 원자, 요오드 원자 등의 할로겐 원자, 또는 메탄술포닐옥시기, p-톨루엔술포닐옥시기 등의 반응성 에스테르기이며, R은 메틸기, 에틸기 등의 저급 알킬기이며, *는 상기와 동일 의미이다.In the formula, W is a leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, or a reactive ester group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and R is a methyl group or an ethyl group. It is a lower alkyl group and * is synonymous with the above.
공정 A는 (S)-피페리딘 중간체(Ⅳ)의 N-알킬화 반응이며, (S)-피페리딘 중간체(Ⅳ) 1몰에 대하여 에스테르(Ⅴ) 1 내지 3배몰, 바람직하게는 1 내지 1.5배몰을 사용하여 행할 수가 있다. 상기 반응은 불활성 용매 중에서 이루어진다. 적당한 용매로서는 예를 들면 물; 메탄올, 에탄올, 프로판올, 부탄올 등의 저급 알코올류; 아세토니트릴, 프로피오니트릴 등의 니트릴류; 벤젠, 톨루엔, 크실렌 등의 방향족 탄화 수소류; 1,4-디옥산, 테트라히드로푸란 등의 에테르류; 아세톤, 에틸메틸케톤, 메틸이소부틸케톤 등의 케톤류; N,N-디메틸포름아미드 등의 아미드류를 들 수 있다. 바람직하게는 물, 아세트니트릴, 아세톤, N,N-디메틸포름아미드이다. 이 용매들은 단독으로 사용하여도 좋고, 임의의 2종류 이상의 용매를 혼합하여 사용하여도 좋다.Process A is an N-alkylation reaction of (S) -piperidine intermediate (IV), with respect to 1 mol of ester (V), preferably 1 to 3 moles of (S) -piperidine intermediate (IV). This can be done using a 1.5 times mole. The reaction is in an inert solvent. Suitable solvents include, for example, water; Lower alcohols such as methanol, ethanol, propanol and butanol; Nitriles such as acetonitrile and propionitrile; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as 1,4-dioxane and tetrahydrofuran; Ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone; Amides, such as N, N- dimethylformamide, are mentioned. Preferably water, acetonitrile, acetone, N, N-dimethylformamide. These solvents may be used alone or in combination of two or more kinds of solvents.
이 반응은 염기 존재하에 행하는 것이 바람직하고, 적당한 염기로서는 예를 들면 수산화 나트륨 등의 알칼리 금속 수산화물; 수산화 칼슘 등의 알칼리 토금속 수산화물; 탄산 칼륨 등의 알칼리 금속 탄산염; 탄산 칼슘 등의 알칼리 토금속 탄산염; 탄산 수소 나트륨 등의 알칼리 금속 탄산수소염; 수소화 나트륨 등의 알칼리 금속 수소화물; 수소화 칼슘 등의 알칼리 토금속 수소화물; 나트륨 메톡시드 등의 알칼리 금속 알콕시드; 트리에틸아민 등의 트리알킬아민 및 피페리딘 화합물 등을 들 수 있으며, 탄산 나트륨, 탄산 칼륨, 탄산 수소 나트륨 또는 탄산 수소 칼륨이 바람직하다. 이러한 염기가 1가의 염기라면 (S)-피페리딘 중간체(Ⅳ) 1몰에 대하여 1 내지 3배몰, 바람직하게는 1 내지 1.5배몰을 사용한다. 2가의 염기라면 0.5 내지 1.5배몰, 바람직하게는 0.6 내지 1배몰을 사용한다.It is preferable to perform this reaction in presence of a base, As a suitable base, For example, alkali metal hydroxides, such as sodium hydroxide; Alkaline earth metal hydroxides such as calcium hydroxide; Alkali metal carbonates such as potassium carbonate; Alkaline earth metal carbonates such as calcium carbonate; Alkali metal hydrogencarbonates such as sodium hydrogen carbonate; Alkali metal hydrides such as sodium hydride; Alkaline earth metal hydrides such as calcium hydride; Alkali metal alkoxides such as sodium methoxide; Trialkylamine, such as triethylamine, and a piperidine compound, etc. are mentioned, A sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate is preferable. If such a base is a monovalent base, 1-3 moles, preferably 1-1.5 moles, per 1 mole of (S) -piperidine intermediate (IV) is used. If it is a divalent base, 0.5-1.5 molar moles, Preferably 0.6-1 molar moles are used.
또한, 반응 촉진제로서 예를 들면 요오드화 나트륨 또는 요오드화 칼륨 등의 소량의 금속 요오드화물을 첨가하여도 좋다. 반응은 반응 혼합물의 환류 온도에서 행할 수가 있으며, 예를 들면 5 내지 150 ℃, 바람직하게는 20 내지 100 ℃이다. 반응 시간은 2 내지 24시간이다.As a reaction accelerator, for example, a small amount of metal iodide such as sodium iodide or potassium iodide may be added. The reaction can be carried out at the reflux temperature of the reaction mixture, for example 5 to 150 ° C, preferably 20 to 100 ° C. The reaction time is 2 to 24 hours.
공정 B는 (S)-에스테르(Ⅵ)의 가수 분해 반응이며, 수성 메탄올, 수성 에탄올 등의 알코올 중에서, 예를 들면 수산화 나트륨, 수산화 칼륨 등의 무기 염기를 (S)-에스테르(Ⅵ) 1몰에 대하여 1 내지 5배몰, 바람직하게는 1 내지 3배몰을 사용할 수가 있다. 반응 온도는 예를 들면 5 내지 90 ℃, 바람직하게는 15 내지 70 ℃이다. 반응 시간은 1 내지 10시간이다. 반응 종료 후, 예를 들면 염산, 황산 등의 무기산 또는 아세트산, 옥살산 등의 유기산으로 반응액을 중화 처리함으로써 (S)-피페리딘 화합물(Ⅰ)을 제조할 수가 있다.Step B is a hydrolysis reaction of (S) -ester (VI), and in an alcohol such as aqueous methanol and aqueous ethanol, for example, 1 mole of (S) -ester (VI) of inorganic base such as sodium hydroxide or potassium hydroxide 1 to 5 times mole with respect to, preferably 1 to 3 times mole can be used. The reaction temperature is, for example, 5 to 90 ° C, preferably 15 to 70 ° C. The reaction time is 1 to 10 hours. After the reaction is completed, the (S) -piperidine compound (I) can be produced by neutralizing the reaction solution, for example, with an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or oxalic acid.
일반적으로 광학 활성체를 취득하기 위해서는 비대칭 합성, 분별 결정 또는 리파아제 등의 효소에 의한 광학 분할, 광학 분할 칼럼에 의한 분취 등의 방법이 알려져 있다. 본 발명에서 광학 활성의 (S)-피페리딘 화합물(Ⅰ)을 효율적으로 제조하기 위해서는 하기 반응식 3으로 표시된 바와 같이, 원료 화합물인 화학식 Ⅲ으로 표시되는 (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 미리 광학 분할하고, 얻어지는 광학 활성인 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 (Ⅳ)을 중간체로서 사용하면 좋다.Generally, in order to acquire an optically active substance, methods, such as asymmetric synthesis, fractional crystal | crystallization, or optical division by enzymes, such as a lipase, and fractionation by an optical division column, are known. In order to efficiently prepare the optically active (S) -piperidine compound (I) in the present invention, as represented by the following Scheme 3, (±) -4-[(4-chloro) Phenyl) (2-pyridyl) methoxy] piperidine in advance is optically divided, and the resulting optically active (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine ( IV) may be used as an intermediate.
식 중, *는 비대칭 탄소를 나타낸다.In the formula, * represents an asymmetric carbon.
상기 광학 분할은 다음에 나타내는 방법에 의해 효율적으로 실시할 수가 있다. 즉, 하기 화학식 Ⅲ으로 표시되는 라세미체형 피페리딘 화합물에 하기 화학식 Ⅶ로 표시되는 광학 활성 프로피온산 화합물(Ⅶ) 또는 광학 활성 N-아실-아미노산을 작용시키고, 생성된 2종의 부분 입체 이성질체 염의 용해도 차이를 이용하여 난용성의 부분 입체 이성질체 염을 분리, 채취하고, 이 염을 분해함으로써 하기 화학식 Ⅳ로 표시되는 광학 활성 피페리딘 중간체(Ⅳ)를 얻을 수가 있다.The said optical division can be performed efficiently by the method shown next. That is, the racemic type piperidine compound represented by the following general formula (III) is reacted with the optically active propionic acid compound (VII) represented by the following general formula (VII) or optically active N-acyl-amino acid, and the two diastereomeric salts produced By using the solubility difference, the poorly soluble diastereomeric salt is separated and collected, and the salt is decomposed to obtain the optically active piperidine intermediate (IV) represented by the following formula (IV).
식 중, Y는 수소 원자 또는 할로겐 원자를 나타내고, Z는 저급 알콕시기를 나타내며, *는 비대칭 탄소를 나타낸다.In the formula, Y represents a hydrogen atom or a halogen atom, Z represents a lower alkoxy group, and * represents an asymmetric carbon.
광학 분할제로서 사용하는 광학 활성 프로피온산 화합물(Ⅶ)의 구체예로서는 화학식 Ⅶ에서, Y가 수소 원자 또는 염소 원자이며, Z가 메톡시기인 화합물을 들 수 있다. 이들 중 바람직한 예로서, (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산, 및 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로페닐티오)프로피온산을 들 수가 있고, 이들 중 특히 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산이 바람직하다.As a specific example of the optically active propionic acid compound (i) used as an optical splitting agent, the compound whose Y is a hydrogen atom or a chlorine atom and Z is a methoxy group is represented by General formula (X). Preferred examples of these include (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid, and (2R, 3R) -2. -Hydroxy-3- (4-methoxyphenyl) -3- (2-nitrophenylthio) propionic acid, among which (2R, 3R) -2-hydroxy-3- (4-methoxy Phenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid is preferred.
또한, 광학 분할제로서 사용하는 광학 활성 N-아실-아미노산의 아실기로서는 아세틸기, 프로피오닐기와 같은 지방족 아실기, 토실기와 같은 방향족 아실기, 벤질옥시카르보닐기와 같은 아르알킬옥시카르보닐기 등을 사용한다. 광학 활성 N-아실-아미노산은 단백질의 구성 성분인 중성, 산성 및 염기성의 각종 L-아미노산 또는 비천연형의 D-아미노산을 통상법에 의해 아실화하여 얻는다. 아미노산으로서는, 바람직하게는 L-페닐알라닌, L-로이신, L-글루타민산, L-메티오닌, L-발린, L-트레오닌 및 D-페닐글리신을 들 수 있다.As the acyl group of the optically active N-acyl-amino acid used as the optical dividing agent, an acetyl group, an aliphatic acyl group such as propionyl group, an aromatic acyl group such as tosyl group, an aralkyloxycarbonyl group such as benzyloxycarbonyl group, etc. are used. do. Optically active N-acyl-amino acids are obtained by acylating, by conventional methods, a variety of neutral, acidic and basic L-amino acids or non-natural D-amino acids that are constituents of the protein. As amino acids, L-phenylalanine, L-leucine, L-glutamic acid, L-methionine, L-valine, L-threonine, and D-phenylglycine are mentioned preferably.
광학 활성 N-아실-아미노산의 바람직한 구체예로서는 N-아세틸-L-페닐알라닌, N-아세틸-L-로이신, N-벤질옥시카르보닐-L-페닐알라닌, N-벤질옥시카르보닐-L-발린, N-벤질옥시카르보닐-L-트레오닌 및 N-벤질옥시카르보닐-L-세린을 들 수 있으며, 보다 바람직하게는 N-아세틸-L-페닐알라닌을 들 수 있다.Preferred embodiments of optically active N-acyl-amino acids include N-acetyl-L-phenylalanine, N-acetyl-L-leucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N -Benzyloxycarbonyl-L-threonine and N-benzyloxycarbonyl-L-serine, and N-acetyl-L-phenylalanine is more preferable.
광학 분할제로서 사용되는 화학식 Ⅶ의 광학 활성 프로피온산 화합물 Ⅶ 또는 광학 활성 N-아실-아미노산의 사용량은 특별히 한정되는 것은 아니지만, 화학식 Ⅲ의 라세미체형 피페리딘 중간체(Ⅲ) 1몰에 대하여 0.5 내지 1.5배몰, 바람직하게는 0.6 내지 1.1배몰울 사용하는 것이 바람직하다.The amount of the optically active propionic acid compound of formula (VII) or optically active N-acyl-amino acid to be used as the optical splitting agent is not particularly limited, but is 0.5 to 1 mole per 1 mole of racemic type piperidine intermediate (III) of formula (III). It is preferable to use 1.5 moles, preferably 0.6 to 1.1 moles.
본 발명에서 원료로서 사용하는 화학식 Ⅲ의 라세미체형 피페리딘 중간체(Ⅲ)는 (S)형 이성질체 및 (R)형 이성질체의 등몰량 혼합물로 충분한데, 이성질체의 혼합비는 반드시 등몰량이 아니어도 좋고, 어느 한쪽이 많이 함유된 혼합물이어도 좋다.The racemic piperidine intermediate (III) of formula (III) used as a raw material in the present invention is sufficient as an equimolar mixture of the (S) isomer and the (R) isomer, but the mixing ratio of the isomers may not necessarily be equimolar. It may be a mixture containing either one a lot.
화학식 Ⅲ의 라세미체형 피페리딘 중간체(Ⅲ)는 염산염과 같은 산부가염을 사용할 수도 있으며, 그 경우, 예를 들면 반응계에 적당한 알칼리(예, 수산화 나트륨)와 같은 염기를 첨가하면 염교환이 일어나 유리된 피페리딘 화합물이 된다. 또한, 화학식 Ⅶ의 광학 활성 프로피온산 화합물(Ⅶ) 또는 광학 활성 N-아실-아미노산으로서는 염기와의 염을 사용할 수가 있으며, 그 경우는 반응계에 염산과 같은 산을 첨가하면 각각 유리된 광학 활성 프로피온산 화합물(Ⅶ) 또는 유리된 광학 활성 N-아실-아미노산이 된다.The racemic type piperidine intermediate (III) of formula (III) may also use acid addition salts such as hydrochloride, in which case salt exchange takes place when, for example, a suitable base (e.g. sodium hydroxide) is added to the reaction system. It is a free piperidine compound. In addition, as an optically active propionic acid compound (VII) of Formula (VII) or an optically active N-acyl-amino acid, a salt with a base can be used. In this case, when an acid such as hydrochloric acid is added to the reaction system, the optically active propionic acid compound ( Viii) or liberated optically active N-acyl-amino acids.
라세미체형 피페리딘 중간체(Ⅲ)의 광학 분할시에 사용되는 용매로서는 메탄올, 에탄올, 프로판올과 같은 알코올류; 아세톤, 메틸에틸케톤과 같은 케톤류; 아세트산메틸, 아세트산에틸과 같은 카르복실산의 에스테르류; 아세토니트릴, 프로피오니트릴과 같은 니트릴류; 디옥산, 테트라히드로푸란과 같은 에테르류; 디메틸포름아미드와 같은 아미드류 또는 물 등을 들 수 있으며, 더욱 특히는 에스테르류, 니트릴류, 알코올류 또는 물이 바람직하며, 특히 알코올류 또는 물이 바람직하다. 이들 용매는 단독으로 사용하여도 좋은데, 필요에 따라 적당한 비율로 2종류 또는 그 이상을 혼합하여 사용하여도 좋으며, 특히 알코올류와 물의 혼합 용매가 바람직하다. 용매의 사용량에 특별한 제한은 없지만, 라세미체형 피페리딘 중간체(Ⅲ) 1 중량부에 대하여, 예를 들면 2 내지 50 중량부, 바람직하게는 5 내지 50 중량부를 사용하면 좋다.As a solvent used at the time of optical division of a racemate type piperidine intermediate (III), Alcohol, such as methanol, ethanol, a propanol; Ketones such as acetone and methyl ethyl ketone; Esters of carboxylic acids such as methyl acetate and ethyl acetate; Nitriles such as acetonitrile and propionitrile; Ethers such as dioxane and tetrahydrofuran; Amides, such as dimethylformamide, or water, etc. are mentioned, More preferably, esters, nitriles, alcohols, or water are preferable, and alcohol or water is especially preferable. Although these solvents may be used independently, you may mix and use two or more types by suitable ratio as needed, Especially the mixed solvent of alcohol and water is preferable. Although there is no restriction | limiting in particular in the usage-amount of a solvent, For example, 2-50 weight part, Preferably 5-50 weight part may be used with respect to 1 weight part of racemic-type piperidine intermediate (III).
광학 분할의 방법에서, 생성되는 2종의 부분 입체 이성질체 염의 용해도의 차이는 충분히 크기 때문에, 특별한 결정화 조작을 하지 않아도 난용성 부분 입체 이성질체 염이 정치 또는 교반하에 반응액에서 용이하게 석출되게 된다.In the method of optical splitting, the difference in solubility of the resulting two diastereomeric salts is sufficiently large, so that poorly soluble diastereomeric salts are easily precipitated in the reaction solution under standing or stirring even without a special crystallization operation.
화학식 Ⅲ의 라세미체형 피페리딘 중간체(Ⅲ)와 화학식 Ⅶ의 광학 활성 프로피온산 화합물(Ⅶ) 또는 광학 활성 N-아실 아미노산의 용매에 대한 용해, 및 계속되는 난용성 부분 입체 이성질체 염의 석출시의 조건에는 특별한 제한은 없지만, 예를 들면 두가지 화합물의 용매에 대한 용해는 가온 내지 가열하에서 실시할 수 있으며, 계속되는 난용성 부분 입체 이성질체 염의 석출은 냉각 내지 가온하에서 실시할 수가 있다.Conditions for dissolution of racemic type piperidine intermediate (III) and optically active propionic acid compound (VII) or optically active N-acyl amino acid of formula (III) in the solvent, and subsequent precipitation of poorly soluble diastereomeric salts There is no particular limitation, but for example, dissolution of the two compounds in the solvent can be carried out under heating to heating, and subsequent precipitation of the poorly soluble diastereomeric salt can be carried out under cooling to heating.
반응액에서 난용성 부분 입체 이성질체 염을 석출시키기 위하여 통상은 종자 결정을 첨가할 필요는 없지만, 석출을 보다 용이하게 하기 위하여 목적하는 부분 입체 이성질체 염과 동종의 결정을 첨가하여도 좋다.It is usually not necessary to add seed crystals in order to precipitate poorly soluble diastereomeric salts from the reaction solution, but in order to facilitate precipitation, crystals of the same type as the desired diastereomeric salts may be added.
또한, 난용성 부분 입체 이성질체 염을 분리한 후의 모액을 농축하여, 가용성 부분 입체 이성질체 염인 다른 부분 입체 이성질체 염을 분리, 채취하고, 이어서 이 염을 분해하거나, 또는 난용성 부분 입체 이성질체 염을 분리한 후의 모액을 적당한 유기 용매로 추출하여 남아 있는 거울상 이성질체인 광학 활성 피페리딘 중간체(Ⅳ)를 회수하여도 좋다.In addition, the mother liquor after separation of the poorly soluble diastereomeric salt is concentrated to separate and extract other diastereomeric salts that are soluble diastereomeric salts, and then decompose the salts or separate the poorly soluble diastereomeric salts. The subsequent mother liquor may be extracted with a suitable organic solvent to recover the optically active piperidine intermediate (IV) which is the remaining enantiomer.
또한 분리, 채취한 부분 입체 이성질체 염은 필요에 따라 재결정함으로써 더욱 순도를 높일 수가 있다.In addition, the purified diastereomeric salt can be further purified by recrystallization as necessary.
이렇게 하여 채취된 부분 입체 이성질체 염은 공지된 염분해 방법에 의해 염을 탈리하여, 목적하는 광학 활성 피페리딘 중간체(Ⅳ)를 얻을 수가 있다. 예를 들면 적당한 용매(예, 물-디메틸포름아미드의 혼합 용액 등)에 용해하고, 적당한 알칼리(예, 수산화 나트륨, 수산화 칼륨 등)로 처리하여, 이것을 적당한 추출 용매(예, 디에틸에테르, 아세트산에틸, 클로로포름, 염화 메틸렌, 톨루엔 등)로 추출한 후, 추출 용매를 증발시킴으로써 광학 활성 피페리딘 중간체(Ⅳ)를 얻을 수가 있다.The diastereomeric salt thus obtained can be desorbed by a known hydrolysis method to obtain the desired optically active piperidine intermediate (IV). For example, it is dissolved in a suitable solvent (e.g., a mixed solution of water-dimethylformamide, etc.) and treated with a suitable alkali (e.g., sodium hydroxide, potassium hydroxide, etc.), which is then extracted with a suitable extraction solvent (e.g., diethyl ether, acetic acid). After extraction with ethyl, chloroform, methylene chloride, toluene and the like), the optically active piperidine intermediate (IV) can be obtained by evaporating the extraction solvent.
또한, 추출 후의 수용액 층을 적당한 무기산(예, 염산, 황산 등)으로 처리한 후, 적당한 용매(예, 디에틸에테르, 아세트산에틸, 클로로포름, 염화 메틸렌, 톨루엔 등)로 추출하면, 광학 분할제인 광학 활성 프로피온산 화합물(Ⅶ) 또는 광학 활성 N-아실-아미노산을 회수할 수가 있다.In addition, the aqueous solution layer after extraction is treated with a suitable inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.), and then extracted with a suitable solvent (e.g. diethyl ether, ethyl acetate, chloroform, methylene chloride, toluene, etc.). The active propionic acid compound (i) or optically active N-acyl-amino acid can be recovered.
광학 분할제로서 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산을 사용한 광학 분할 방법에 의한 구체적인 예를 하기에 나타낸다.Specific examples by the optical splitting method using (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid as the optical splitting agent Shown in
즉, (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘에 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산(광학 분할제)을 작용시켜, 난용성 부분 입체 이성질체 염으로서 석출되는 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산의 염을 분리, 채취하고, 이어서 이 염을 분해하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 얻는다.Namely, (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine to (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3 (S) -4-[(4-chlorophenyl) (2-pyridyl), precipitated as a poorly soluble diastereomeric salt by reacting-(2-nitro-5-chlorophenylthio) propionic acid (optical splitting agent) Methoxy] piperidine and a salt of (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid are separated and collected, This salt is then decomposed to give (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
본 명세서 중, 난용성 부분 입체 이성질체 염이란 한 쌍의 부분 입체 이성질체 염 중, 용매에 대한 용해도가 보다 낮은 부분 입체 이성질체 염을 의미한다.In the present specification, the poorly soluble diastereomeric salt means a diastereomeric salt having lower solubility in a solvent among a pair of diastereomeric salts.
또한, 원료인 화학식 Ⅲ의 라세미체형 피레리딘 중간체(Ⅲ)는 일본 특허공개평 2-25465호 공보에 기재되어 있다. 광학 분할제인 화학식 Ⅶ의 광학 활성 프로피온산 화합물(Ⅶ)은 예를 들면 특공소 63-13994호 공보에 기재된 방법에 준하여 제조할 수가 있다.In addition, racemic pyreridine intermediate (III) of general formula (III) which is a raw material is described in Unexamined-Japanese-Patent No. 2-25465. The optically active propionic acid compound (VIII) of general formula (X) which is an optical splitting agent can be manufactured according to the method of Unexamined-Japanese-Patent No. 63-13994, for example.
(약리 시험)(Pharmacological test)
다음의 광학 활성 피페리딘 에스테르 화합물의 (S)-에스테르 및 (R)-에스테르를 사용하여 광학 이성질체간의 약리 작용의 차이를 시험하였다.The difference in pharmacological action between the optical isomers was tested using (S) -ester and (R) -ester of the following optically active piperidine ester compounds.
(S)-에스테르: (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염(참고예 3에서 제조)(S) -ester: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethylfumarate (prepared in Reference Example 3)
(R)-에스테르: (R)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염(참고예 4에서 제조)(R) -ester: (R) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethylfumarate (prepared in Reference Example 4)
<히스타민 쇼크사 억제 작용><Histamine shock company inhibitory action>
체중 250 내지 550 g의 하틀리(Hartley)계 암컷 몰모트를 사용하고, 랜즈(Lands) 등의 방법[Lands, A.M., Hoppe, J.O., Siegmund, O.H. 및 Luduena, F.F., J.Pharmacol. Exp. Ther., 95, 45(1949)]에 준하여 히스타민 쇼크사 억제 작용을 시험하였다. 실험 동물을 하룻밤(약 14 시간) 절식시킨 후, 시험 물질 5 ㎖/㎏을 경구 투여하였다. 시험 물질 투여 2시간 후에 히스타민 염산염 1.25 mg/㎏을 정맥 투여하여 히스타민 쇼크를 유발시켰다. 유발 후, 실험 동물의 증상을 관찰하고, 히스타민 쇼크의 발현 시간을 측정하고, 호흡 정지 또는 회복까지를 관찰하였다. 시험 결과를 표 1에 나타냈다.Using a Hartley-based female molemot with a body weight of 250 to 550 g, Lands et al. [Lands, A.M., Hoppe, J.O., Siegmund, O.H. And Luduena, F. F., J. Pharmacol. Exp. Ther., 95, 45 (1949)] was tested for histamine shock. The experimental animals were fasted overnight (about 14 hours) and then orally administered 5 ml / kg of test substance. Two hours after test substance administration, 1.25 mg / kg of histamine hydrochloride was administered intravenously to induce histamine shock. After induction, the symptoms of the experimental animals were observed, the expression time of histamine shock was measured, and respiration was stopped or recovered. The test results are shown in Table 1.
<7일간 상동성 (homologous) PCA 반응 억제 작용>Inhibition of homologous PCA response for 7 days
체중 250 내지 550 g의 하틀리계 암컷 몰모트를 사용하고, 레빈(Levine) 등의 방법[Levine, B.B., Chang, Jr.H., 및 Vaz,N.M., J.Immunol., 106, 29(1971)]에 준하여 PCA 반응 억제 작용을 시험하였다. 전날에 털을 깍은 몰모트의 등 한가운데 선을 사이에 두고 좌우 두점에 생리 식염수로 32배 희석한 몰모트 항 BPO·BGG-IgE 혈청 0.05 ㎖를 피하내 투여하였다.Methods of Levine et al. (Levine, BB, Chang, Jr. H., and Vaz, NM, J. Immunol., 106, 29 (1971)) using Hartley-based female malmots of 250-550 g body weight PCA response inhibitory action was tested according to the procedure. On the day before, 0.05 ml of the malmot anti-BPO-BGG-IgE serum diluted 32-fold with physiological saline was administered subcutaneously to the left and right points between the lines in the middle of the back of the molted molar.
7일 후에 항원으로서 벤질페니실로일 소혈청 알부민(BPO·BSA) 500 ㎍을 함유하는 1 % 에반스 블루(Evans Blue) 생리 식염수 1 ㎖를 정맥내 투여하여 PCA 반응을 야기시켰다. 30분 후에 방혈하고, 피부를 박리하여 누출된 색소량을 가따야마(Katayama) 등의 방법[Katayama, S., Shinoya, H. 및 Ohtake, S., Microbiol. Immunol., 22, 89 (1978)]에 준하여 측정하였다. 실험 동물은 하룻밤(약 16시간) 절식시키고, 시험 물질은 항원 투여 2시간 전에 경구 투여하였다. 시험 결과를 표 2에 나타냈다.After 7 days 1 ml of 1% Evans Blue physiological saline containing 500 μg of benzylphenicyl yl bovine serum albumin (BPO.BSA) as an antigen was administered intravenously to cause a PCA response. After 30 minutes, the blood was bleeded, the skin was peeled off, and the amount of leaked pigment was measured by Katayama et al. [Katayama, S., Shinoya, H. and Ohtake, S., Microbiol. Immunol., 22, 89 (1978)]. The experimental animals were fasted overnight (about 16 hours) and the test substance was administered orally 2 hours before antigen administration. The test results are shown in Table 2.
표 1의 시험 결과에서 (S)-에스테르 및 (R)-에스테르는 모두 용량 의존적인 억제 작용을 나타내며, 용량 반응 곡선으로 구한 (S)-에스테르 및 (R)-에스테르의 ED50값은 각각 0.023 ㎎/㎏ 및 1.0 ㎎/㎏이며, (S)-에스테르는 (R)-에스테르보다 약 43배 강한 활성을 나타냈다. 또한, 표 2에 나타내는 PCA 반응 억제 시험에서도 (S)-에스테르 및 (R)-에스테르는 모두 용량 의존적으로 반응을 억제하였다. 이 시험에서의 최대 억제율은 70 % 정도라고 추정되며, 최대치의 50 %(즉 35 %)를 억제하는 투여량으로 비교하면, (S)-에스테르는 (R)-에스테르보다 약 100배 이상 강한 작용을 나타냈다. 이것으로 미루어보아 광학 이성질체간에서 분명한 약리 작용의 차이가 발견되었고, (S)-에스테르가 (R)-에스테르보다 우수하다는 것이 확인되었다.In the test results of Table 1, both (S) -ester and (R) -ester showed dose dependent inhibitory action, and ED 50 values of (S) -ester and (R) -ester obtained from dose response curves were 0.023, respectively. Mg / kg and 1.0 mg / kg, and the (S) -ester showed about 43 times stronger activity than the (R) -ester. In addition, in the PCA reaction inhibition test shown in Table 2, both (S) -ester and (R) -ester suppressed the reaction in a dose-dependent manner. The maximum inhibition rate in this test is estimated to be about 70%, and compared with doses that inhibit 50% (ie 35%) of the maximum, the (S) -ester is about 100 times stronger than the (R) -ester. Indicated. From this, a clear difference in pharmacological action was found between the optical isomers and it was confirmed that the (S) -ester was superior to the (R) -ester.
그러나, 상기 (S)-에스테르는 후술하는 안정성 시험 결과(표 4)에 나타내는 바와 같이 흡습성이며, (S)-에스테르의 대사물인 화학식 Ⅰ의 (S)-피페리딘 화합물은 (S)-에스테와 동등한 약리 작용을 나타내는데, 그 자체는 매우 결정성이 나쁜 화합물로, 통상은 호박색 시럽으로서 얻어져, 의약품으로서 고도한 품질을 확보, 유지하기는 곤란하였다.However, the (S) -ester is hygroscopic, as shown in the stability test results (Table 4) described later, and the (S) -piperidine compound of formula (I), which is a metabolite of (S) -ester, is (S) -ester Although it shows a pharmacological action equivalent to, the compound itself is very poor in crystallinity, usually obtained as amber syrup, and it is difficult to secure and maintain high quality as a medicine.
그래서, 화학식 Ⅰ의 (S)-피페리딘 화합물(Ⅰ)의 각종 산부가염에 대하여 다음 방법으로 결정화를 검토하였다.Therefore, crystallization was examined for the various acid addition salts of the (S) -piperidine compound (I) of the general formula (I) by the following method.
(실험예 1)Experimental Example 1
화학식 Ⅰ의 (S)-피페리딘 화합물(Ⅰ)을 유기 용매에 용해하고, 표 3에 나타내는 산을 첨가하여 균일하게 한 후 방치하였다. 석출물이 얻어지지 않는 경우에는 용매를 제거한 후, 난용성의 용매를 첨가하여 다시 방치하였다. 산부가염이 유상 또는 시럽 상태인 경우를 제외하고, 얻어진 고형물을 여과하여 모아서 감압 건조하였다. 얻어진 각종 산부가염의 성상은 표 3에 나타내는 바와 같이 대부분은 유상물 또는 흡습성의 결정이었다.The (S) -piperidine compound (I) of the formula (I) was dissolved in an organic solvent, homogenized by addition of the acid shown in Table 3 and left to stand. In the case where a precipitate was not obtained, the solvent was removed, followed by addition of a poorly soluble solvent and left to stand again. The solids obtained were collected by filtration and dried under reduced pressure, except when the acid addition salt was in the oily or syrup state. As shown in Table 3, most of the obtained acid addition salts were oily substances or hygroscopic crystals.
그러나, 화학식 Ⅰ의 (S)-피페리딘 화합물(Ⅰ)의 벤젠술폰산염 및 벤조산염은 흡습성이 아닌 결정으로서 얻어졌다.However, benzenesulfonate and benzoate of (S) -piperidine compound (I) of formula (I) were obtained as crystals which are not hygroscopic.
(안정성 시험)(Stability test)
벤젠술폰산염: (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산-벤젠술폰산염(실시예 2에서 제조)Benzenesulfonate: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid-benzenesulfonate (prepared in Example 2)
벤조산염: (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산-벤조산염(실시예 3에서 제조)Benzoate: (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid-benzoate (prepared in Example 3)
상기 각 화합물을 분쇄한 후, 500 ㎛의 체를 통과시킨 것을 시험 재료로 하였다. 각 시료를 유리 샤알레에 분할하여 넣고, 40 ℃, 75 % 습도로 보존하여 1개월 후에 꺼내 함유 유사 물질량 및 라세미체화에 의한 (R)-이성질체 함유량을 측정하고, 시험 개시시의 함유량과 비교하였다.After pulverizing each compound, a test material was used, which was passed through a 500 μm sieve. Each sample was divided into glass shales, stored at 40 ° C. and 75% humidity, and taken out after one month. The amount of similar substances contained and the (R) -isomer content by racemization were measured and compared with the contents at the start of the test. It was.
(a) 유사 물질의 함유량 변화(a) change in content of analogues
시료를 이동상에 녹이고, 이 용액 1 ㎖ 중에 시료 약 0.1 %가 함유되도록 조제하였다. 시료 용액 25 ㎕에 대하여 액체 크로마토그래피로 각각의 피크 면적 백분율을 자동 적분법으로 측정하였다.The sample was dissolved in a mobile phase and prepared to contain about 0.1% of the sample in 1 ml of this solution. For each 25 μl of sample solution, the percentage of each peak area was determined by automatic integration by liquid chromatography.
<조작 조건><Operation conditions>
검출기: 자외선 흡광 광도계(225 nm)Detector: UV Absorbance Photometer (225 nm)
칼럼: Cosmosil 5 ph 4.6 ㎜×150 ㎜(상품명, Nakarai Tesc Co. 제품)Column: Cosmosil 5 ph 4.6 mm x 150 mm (trade name, manufactured by Nakarai Tesc Co.)
칼럼 온도: 실온Column temperature: room temperature
이동상:Mobile phase:
(S)-에스테르: 0.01 M 인산 이수소 칼륨 완충액(0.1 N 수산화 나트륨 용액으로 pH 5.8로 조정)과 아세토니트릴의 혼합액(65:35)(S) -ester: a mixture of 0.01 M potassium dihydrogen phosphate buffer (adjusted to pH 5.8 with 0.1 N sodium hydroxide solution) and acetonitrile (65:35)
벤젠술폰산염, 벤조산염: 0.01 M 인산 이수소 칼륨 완충액(0.1 N 수산화 나트륨 용액으로 pH 5.8로 조정)과 아세토니트릴의 혼합액(72:28)Benzenesulfonate, benzoate: a mixture of 0.01 M potassium dihydrogen phosphate buffer (adjusted to pH 5.8 with 0.1 N sodium hydroxide solution) and acetonitrile (72:28)
유량: 0.9 ㎖/분Flow rate: 0.9 ml / min
피크 면적 측정 범위: 시료 주입후 50분 이내의 범위Peak area measurement range: within 50 minutes after sample injection
(b) (R)-이성질체의 양(b) amount of (R) -isomer
시료 약 5 ㎎을 이동상에 녹이고, 이 용액 1 ㎖ 중에 시료 약 0.1 %가 함유되도록 조제하였다. 시료 용액 1.5 ㎕에 대하여 액체 크로마토그래피법으로 각각의 피크 면적 백분율을 자동 적분법으로 측정하고, 하기 수학식으로 (R)-이성질체의 양(%)을 산출하였다.About 5 mg of sample was dissolved in a mobile phase, and 1 ml of this solution was prepared to contain about 0.1% of the sample. Each peak area percentage was measured by the automatic integration method with respect to 1.5 µl of the sample solution, and the amount (%) of the (R) -isomer was calculated by the following equation.
QS: (S)-이성질체의 피크 면적 백분율Q S : Peak area percentage of (S) -isomer
QR: (R)-이성질체의 피크 면적 백분율Q R : Peak area percentage of (R) -isomer
<조작 조건><Operation conditions>
검출기: 자외선 흡광 광도계(220 nm)Detector: ultraviolet absorbance photometer (220 nm)
칼럼: ULTRONES-OVM 4.6 ㎜×150 ㎜(상품명, Shinwa Kako Co. 제품)Column: ULTRONES-OVM 4.6 mm x 150 mm (brand name, manufactured by Shinwa Kako Co.)
칼럼 온도: 실온Column temperature: room temperature
이동상:Mobile phase:
(S)-에스테르: 0.02 M 인산 이수소 칼륨 완충액(0.1 N 수산화 나트륨 용액으로 pH 4.6으로 조정)과 에탄올의 혼합액(100:13)(S) -ester: a mixture of 0.02 M potassium dihydrogen phosphate buffer (adjusted to pH 4.6 with 0.1 N sodium hydroxide solution) and ethanol (100: 13)
벤젠술폰산염, 벤조산염: 0.02 M 인산 이수소 칼륨 완충액(0.1 N 수산화 나트륨 용액으로 pH 5.5로 조정)과 아세토니트릴의 혼합액(100:16)Benzenesulfonate, benzoate: a mixture of 0.02 M potassium dihydrogen phosphate buffer (adjusted to pH 5.5 with 0.1 N sodium hydroxide solution) and acetonitrile (100: 16)
유량: 0.9 ㎖/분Flow rate: 0.9 ml / min
면적 측정 범위: (S)-이성질체 체류 시간의 약 2배의 범위Area measurement range: approximately twice the (S) -isomer residence time
체류 시간: (R)-이성질체 약 7 내지 10 분Retention time: about 7 to 10 minutes of the (R) -isomer
(S)-이성질체 약 13 내지 15 분 (S) -isomer about 13-15 minutes
표 4의 시험 결과로부터 (S)-에스테르는 분해에 의해 유사 물질의 증가가 현저히 발견되었으며, (R)-이성질체 양의 증가에 따라 광학 순도가 저하된다는 것이 밝혀졌다. 따라서, (S)-에스테르는 물리 화학적으로 불안정한 화합물이며, 의약품으로서 장기간 고도한 품질을 확보할 수 있다고는 하기 어렵다. 한편, 벤젠술폰산염 및 벤조산염은 유사 물질 및 (R)-이성질체 양의 현저한 증가는 발견되지 않았으며, 흡습성도 적다는 것이 확인되었다. 따라서, 이들 염은 광학 활성체로서 물리 화학적인 안정성을 갖는 화합물이다.From the test results in Table 4, it was found that the (S) -ester was markedly increased in analogous material by decomposition, and the optical purity was lowered with the increase in the amount of (R) -isomer. Therefore, (S) -ester is a physicochemically unstable compound, and it is difficult to say that it can secure high quality for a long time as a medicine. On the other hand, benzenesulfonate and benzoate were not found to have a significant increase in the amount of analogues and (R) -isomers and were found to be less hygroscopic. Therefore, these salts are compounds having physicochemical stability as optically active agents.
이상과 같이, (S)-피페리딘 화합물(Ⅰ)의 벤젠술폰산염 및 벤조산염은 항히스타민 활성 및 항알레르기 활성을 갖는 보다 우수한 광학 활성체이고, 생체내에서 활성 본체로서 작용하며, 물리 화학적으로 우수한 안정성을 나타내므로 의약품으로서 적합한 성질을 갖는 것이다.As described above, the benzenesulfonate and benzoate of the (S) -piperidine compound (I) are better optically active agents having antihistamine activity and antiallergic activity, act as active bodies in vivo, and physically and chemically Since it shows excellent stability, it has a suitable property as a medicine.
<실시예><Example>
이하에 참고예 및 실시예를 나타내어 본 발명을 더욱 상세히 설명하는데, 본 발명의 범위는 이들로 한정되는 것은 아니다.The present invention will be described in more detail with reference to Examples and Examples below, but the scope of the present invention is not limited thereto.
<참고예 1>Reference Example 1
(S)-(-)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘(S)-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine
(1) (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 18.58 g(61.36 mmol)을 아세트산메틸 1,000 ㎖에 가열 용해하고 (-)-디벤조일-L-타르타르산-수화물 6.93 g(18.42 mmol)을 첨가하여 교반하였다. 백색 석출 결정(결정 1)을 여과하여 모으고, 여액을 감압하에 농축하였다. 여액을 100 ㎖로 농축하고, 다시 석출된 백색 결정(결정 2)을 여과하여 모은 후, 다시 여액을 감압하에 농축시켰다. 얻어진 결정 및 여액 농축물에 대하여 각각 광학 이성질체의 조성비((S)-이성질체:(R)-이성질체)를 광학 분할 칼럼을 사용한 고성능 액체 크로마토그래프법으로 측정하였다.(1) 18.58 g (61.36 mmol) of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine was dissolved in 1,000 ml of methyl acetate and dissolved in (-)-dibenzoyl- 6.93 g (18.42 mmol) of L-tartaric acid-hydrate were added and stirred. White precipitated crystals (crystal 1) were collected by filtration, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated to 100 mL, and the precipitated white crystals (crystal 2) were again collected by filtration, and then the filtrate was concentrated under reduced pressure. The composition ratio ((S) -isomer: (R) -isomer) of the optical isomer was measured by the high performance liquid chromatograph method using the optical partition column with respect to the obtained crystal and filtrate concentrate, respectively.
결정 1: 18.37 g((S)-이성질체:(R)-이성질체=29.51:70.49)Crystal 1: 18.37 g ((S) -isomer: (R) -isomer = 29.51: 70.49)
결정 2: 0.57 g((S)-이성질체:(R)-이성질체=33.42:66.58)Crystal 2: 0.57 g ((S) -isomer: (R) -isomer = 33.42: 66.58)
여액 농축물: 7.70 g((S)-이성질체:(R)-이성질체=79.94:20.06)Filtrate concentrate: 7.70 g ((S) -isomer: (R) -isomer = 79.94: 20.06)
(2) 상술한 (1)에서 얻어진 여액 농축물 7.70 g(25.43 mmol)을 에탄올 280 ㎖로 가열 용해하고, L-(+)-타르타르산 3.82 g(25.45 mmol)을 첨가하고 다시 가열하여 균일 용액으로 하였다. 서서히 냉각시킨 후, 소량의 종자 결정을 첨가하여 방치하였다. 석출 결정을 여과에 의해 모아서 40 ℃에서 감압 건조하였다. 수득량 8.68 g((S)-이성질체:(R)-이성질체=87.44:12.56)(2) 7.70 g (25.43 mmol) of the filtrate concentrate obtained in (1) above was dissolved in 280 mL of ethanol, and 3.82 g (25.45 mmol) of L-(+)-tartaric acid was added thereto and heated again to obtain a homogeneous solution. It was. After cooling slowly, a small amount of seed crystals was added and left to stand. The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. Yield 8.68 g ((S) -isomer: (R) -isomer = 87.44: 12.56)
(3) 상술한 (2)에서 얻어진 백색 결정 8.68 g에 대하여 (S)-이성질체의 순도가 99.5 %(광학 순도: 99.0 % d.e.)를 초과할 때까지 에탄올 재결정을 반복하였다.(3) For 8.68 g of the white crystal obtained in (2) above, ethanol recrystallization was repeated until the purity of the (S) -isomer exceeded 99.5% (optical purity: 99.0% d.e.).
수득량 3.87 g((S)-이성질체:(R)-이성질체=99.72:0.28)Yield 3.87 g ((S) -isomer: (R) -isomer = 99.72: 0.28)
(4) 상술한 (3)에서 얻어진 백색 결정 2.13 g(4.70 mmol)에 1 N 수산화 나트륨 수용액 15 ㎖을 첨가하고, 클로로포름 약 50 ㎖로 추출하였다. 추출액을 물로 세정한 후 무수 황산 나트륨으로 건조하고 농축하여 목적하는 (S)-(-)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 담황색 유상물로서 얻었다. 수득량 1.40 g(수율:98.6 %).(4) To 2.13 g (4.70 mmol) of the white crystals obtained in (3) above, 15 mL of an aqueous 1 N sodium hydroxide solution was added, followed by extraction with about 50 mL of chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give the desired (S)-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine as pale yellow oil. Got it. Yield 1.40 g (yield: 98.6%).
[α]D 24-10.0°(c=1, MeOH)[α] D 24 -10.0 ° (c = 1, MeOH)
<참고예 2>Reference Example 2
(R)-(+)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘(R)-(+)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine
(1) 참고예(1)에서 얻어진 결정 1에 0.5 N 수산화 나트륨 수용액 200 ㎖를 첨가하고, 톨루엔 약 100 ㎖로 2회 추출하였다. 추출액을 포화 식염수로 세정한 후 무수 황산 나트륨으로 건조하고 농축하여 담황색 유상물 10.29 g을 얻었다.(1) 200 mL of 0.5 N aqueous sodium hydroxide solution was added to Crystal 1 obtained in Reference Example (1), and extracted twice with about 100 mL of toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 10.29 g of a pale yellow oil.
(2) 상술한 (1)에서 얻어진 담황색 유상물 10.29 g을 아세트산메틸 500 ㎖에 가열 용해하고, (+)-디벤조일-D-타르타르산-수화물 1.96 g(5.21 mmol)을 첨가하여 교반하였다. 백색 석출 결정을 여과하여 모으고, 여액을 감압하에 농축하였다. 얻어진 결정 및 여액 농축물에 대하여 각각 광학 이성질체의 조성비 ((S)-이성질체:(R)-이성질체)를 광학 분할 칼럼을 사용하여 고성능 액체 크로마토그래피로 측정하였다.(2) 10.29 g of the pale yellow oil obtained in (1) above was dissolved in 500 ml of methyl acetate, and 1.96 g (5.21 mmol) of (+)-dibenzoyl-D-tartaric acid-hydrate was added and stirred. The white precipitated crystals were collected by filtration and the filtrate was concentrated under reduced pressure. The composition ratio ((S) -isomer: (R) -isomer) of the optical isomers, respectively, for the obtained crystals and the filtrate concentrate was measured by high performance liquid chromatography using an optical splitting column.
백색 결정: 4.31 g((S)-이성질체:(R)-이성질체=65.52:34.48)White crystals: 4.31 g ((S) -isomer: (R) -isomer = 65.52: 34.48)
여액 농축물: 7.93 g((S)-이성질체:(R)-이성질체=16.61:83.39)Filtrate Concentrate: 7.93 g ((S) -isomer: (R) -isomer = 16.61: 83.39)
(3) 상술한 (2)에서 얻어진 여액 농축물 7.90 g(26.09 mmol)과 D-(-)-타르타르산 3.90 g(25.98 mmol)을 에탄올 400 ㎖로 가열 용해하고, 실온에서 하룻밤 방치하였다. 석출 결정을 여과하여 모으고, 40 ℃에서 감압 건조하였다. 수득량 8.56 g((S)-이성질체:(R)-이성질체=9.05:90.95).(3) 7.90 g (26.09 mmol) of the filtrate concentrate obtained in (2) and 3.90 g (25.98 mmol) of D-(-)-tartaric acid were dissolved by heating with 400 ml of ethanol and allowed to stand at room temperature overnight. Precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. Yield 8.56 g ((S) -isomer: (R) -isomer = 9.05: 90.95).
(4) 상술한 (3)에서 얻어진 백색 결정 8.55 g에 대하여 (R)-이성질체의 순도가 99.5 %(광학 순도:99.0 % d.e.)를 초과할 때까지 에탄올 재결정을 반복하였다. 수득량 4.15 g((S)-이성질체:(R)-이성질체=0.24:99.76).(4) To 8.55 g of the white crystal obtained in (3) above, ethanol recrystallization was repeated until the purity of the (R) -isomer exceeded 99.5% (optical purity: 99.0% d.e.). Yield 4.15 g ((S) -isomer: (R) -isomer = 0.24: 99.76).
(5) 상술한 (4)에서 얻어진 백색 결정 4.00 g(8.83 mmol)에 1 N 수산화 나트륨 수용액 15 ㎖를 첨가하고, 클로로포름 약 50 ㎖로 추출하였다. 추출액을 물로 세정한 후, 무수 황산 나트륨으로 건조하고 농축하여 목적하는 (R)-(+)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 담황색 유상물로서 얻었다. 수득량: 2.66 g(수율:99.6 %).(5) To 4.00 g (8.83 mmol) of the white crystals obtained in (4) above, 15 mL of an aqueous 1 N sodium hydroxide solution was added, followed by extraction with about 50 mL of chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give the desired (R)-(+)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine as pale yellow oil. Obtained as. Yield: 2.66 g (yield: 99.6%).
[α]D 23.5+12.2°(c=2, MeOH)[α] D 23.5 + 12.2 ° (c = 2, MeOH)
<참고예 3>Reference Example 3
(S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염의 합성Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl fumarate
(1) 참고예(1)에 따라 얻어진 (S)-(-)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 1.33 g(4.39 mmol, 광학 순도: 99.4 % e.e.)을 아세톤 15 ㎖에 용해하고, 4-브로모부탄산 에틸 1.03 g(5.28 mmol)과 탄산 칼륨 0.73 g(5.28 mmol)을 첨가하여 7시간 교반하면서 가열하였다. 불용물을 여과하고, 여액을 감압하에 농축하여, 얻어진 미황색 유상물을 클로로포름과 메탄올(용량비 30:1)의 혼합 용매를 전개 용매로 하는 실리카겔 칼럼 크로마토그래피로 분리하였다. 단리된 목적 화합물의 분획을 감압하에 농축하여 유상물인 (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸 1.71 g(수율: 93.4 %, 광학 순도: 99.4 % e.e.)을 얻었다.(1) 1.33 g (4.39 mmol, optical purity: 99.4 (S)-(-)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine obtained according to Reference Example (1) % ee) was dissolved in 15 ml of acetone, 1.03 g (5.28 mmol) of ethyl 4-bromobutanoate and 0.73 g (5.28 mmol) of potassium carbonate were added and heated with stirring for 7 hours. The insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the pale yellow oily substance obtained was separated by silica gel column chromatography using a mixed solvent of chloroform and methanol (volume ratio 30: 1) as a developing solvent. The fraction of the isolated desired compound was concentrated under reduced pressure to yield 1.71 g of ethyl (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl butyrate as an oil (yield: 93.4%, optical purity: 99.4% ee).
[α]D 25 - 6.6°(c=1, MeOH) [α] D 25 - 6.6 ° (c = 1, MeOH)
(2) 상술한 (1)에서 얻어진 에틸에스테르 1.70 g(4.08 mmol)과 푸마르산 0.48 g(4.14 mmol)을 에탄올 40 ㎖에 용해시켜 균일 용액으로 만든 후, 혼합 용액을 감압하에 농축하였다. 잔류물에 아세트산에틸 18 ㎖을 첨가하여 다시 균일 용액으로 만들고, 소량의 종자 결정을 첨가하여 하룻밤 방치하였다. 석출 결정을 여과하여 모아서 목적하는 (S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염 1.97 g(수율: 90.1 %, 광학 순도: 99.0 % e. e.)을 얻었다. 융점 123 내지 124 ℃(2) 1.70 g (4.08 mmol) of ethyl ester obtained in (1) and 0.48 g (4.14 mmol) of fumaric acid were dissolved in 40 ml of ethanol to obtain a homogeneous solution, and then the mixed solution was concentrated under reduced pressure. 18 ml of ethyl acetate was added to the residue to make a homogeneous solution, and a small amount of seed crystals was added and left overnight. The precipitated crystals were collected by filtration to obtain 1.97 g of the desired (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid ethyl fumarate (yield: 90.1%, Optical purity: 99.0% ee). Melting point 123-124 ° C
원소 분석값(%): C22H29ClN2O3·C4H4O 4로 하여Elemental analysis value (%): In to a C 22 H 29 ClN 2 O 3 · C 4 H 4 O 4
계산값: C 60.84, H 6.24, N 5.26Calculated Value: C 60.84, H 6.24, N 5.26
실측값: C 60.73, H 6.32, N 5.21Found: C 60.73, H 6.32, N 5.21
<참고예 4>Reference Example 4
(R)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염의 합성Synthesis of (R) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl fumarate
(1) 참고예 2에 따라 얻어진 (R)-(+)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘(광학 순도: 99.5 % e.e.)을 사용하고, 참고예 3의 (1)과 마찬가지 방법으로 (R)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸(광학 순도: 99.5 % e.e.)을 얻었다. [α]D 25 + 6.6°(c=1, MeOH)(1) Using (R)-(+)-4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (optical purity: 99.5% ee) obtained according to Reference Example 2, In the same manner as in (1) of Reference Example 3, (R) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl butanoate (optical purity: 99.5% ee ) [α] D 25 + 6.6 ° (c = 1, MeOH)
(2) 상술한 (1)에서 얻어진 에틸에스테르를 사용하여 참고예 3의 (2)와 마찬가지 방법으로 (R)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸푸마르산염(광학 순도: 99.3 % e.e.)을 얻었다. 융점: 117 내지 119 ℃(2) (R) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy in the same manner as in (2) of Reference Example 3 using the ethyl ester obtained in (1) above ] Piperidino] butanoic acid ethylfumarate (optical purity: 99.3% ee) was obtained. Melting point: 117 to 119 캜
원소 분석값(%): C22H29ClN2O3·C4H4O 4로 하여Elemental analysis value (%): In to a C 22 H 29 ClN 2 O 3 · C 4 H 4 O 4
계산값: C 60.84, H 6.24, N 5.26Calculated Value: C 60.84, H 6.24, N 5.26
실측값: C 60.65, H 6.11, N 5.06Found: C 60.65, H 6.11, N 5.06
<실시예 1><Example 1>
(S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산의 합성Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid
참고예 3(1)에 따라 얻어진 (S)-4-[4-(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 에틸 126.0 g(0.302 mol)을 에탄올 760 ㎖에 용해하고, 5 N 수산화 나트륨 수용액 120.8 ㎖를 첨가하여 실온에서 하룻밤 방치하였다. 원료의 소실을 확인한 후, 5 N 염산 121.1 ㎖를 첨가하여 중화하였다. 석출염을 여과로 제거한 후, 반응 혼합물을 감압하에 농축하고 아세트산메틸 600 ㎖를 첨가하여 다시 감압하에 농축하였다. 잔류물을 디클로로메탄 600 ㎖에 용해하고, 무수 황산 마그네슘으로 충분히 건조하였다. 불용물을 여과로 제거한 후, 여액을 농축하여 목적물을 호박색 시럽(125.3 g)으로서 얻었다. 이 시럽을 다시 감압하에 건조했더니 발포체(120.0 g)가 되었다.760 mL of ethanol (12) of ethyl (S) -4- [4- (4-chlorophenyl) (2-pyridyl) methoxy] piperidino] ethyl butyrate obtained according to Reference Example 3 (1) (0.302 mol) Was dissolved in, and 120.8 ml of 5N aqueous sodium hydroxide solution was added, and the mixture was allowed to stand at room temperature overnight. After confirming the disappearance of the raw materials, it was neutralized by adding 121.1 ml of 5N hydrochloric acid. After the precipitated salt was removed by filtration, the reaction mixture was concentrated under reduced pressure, 600 ml of methyl acetate was added, and again under reduced pressure. The residue was dissolved in 600 mL of dichloromethane and dried sufficiently with anhydrous magnesium sulfate. After insolubles were removed by filtration, the filtrate was concentrated to give the desired product as amber syrup (125.3 g). The syrup was dried again under reduced pressure to give a foam (120.0 g).
[α]D 25+3.4°(c=5, MeOH)[α] D 25 + 3.4 ° (c = 5, MeOH)
<실시예 2><Example 2>
(S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산-벤젠술폰산염의 합성Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid-benzenesulfonate
실시예 1에 따라 얻어진 (S)-4-[4-(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 0.5 g(1.29 mol)을 아세트산에틸 25 ㎖에 용해하고, 벤젠술폰산-수화물 0.20 g(1.14 mmol)을 첨가하여 감압하에 농축하였다. 잔류물에 다시 아세트산에틸 25 ㎖를 첨가하여 약 1주간 방치했더니, 시럽의 일부가 결정화되었다. 스파츌러로 뒤섞어, 다시 방치했더니 전체가 결정화되었다. 이 결정을 아세토니트릴 5 ㎖로 재결정하여 목적물 0.42 g(수율:67.3 %, 광학 순도: 99.2% e.e.)을 담회색 프리즘 결정으로서 얻었다.0.5 g (1.29 mol) of (S) -4- [4- (4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid obtained according to Example 1 was dissolved in 25 ml of ethyl acetate, 0.20 g (1.14 mmol) of benzenesulfonic acid-hydrate was added and concentrated under reduced pressure. 25 ml of ethyl acetate was added to the residue and left for about 1 week, and a part of the syrup crystallized. Stirred with spatula and left again, the whole crystallized. This crystal was recrystallized with 5 ml of acetonitrile to obtain 0.42 g (yield: 67.3%, optical purity: 99.2% e.e.) of the target substance as a light gray prism crystal.
[α]D 20+6.0°(c=5, MeOH). 융점: 161 내지 163 ℃α D 20 + 6.0 ° (c = 5, MeOH). Melting point: 161 to 163 ° C
원소 분석값(%): C21H26ClN2O3·C6H7O 3S로 하여Elemental analysis value (%): C 21 H 26 ClN 2 O 3 · to a C 6 H 7 O 3 S
계산값: C 59.28, H 5.71, N 5.12Calculated Value: C 59.28, H 5.71, N 5.12
실측값: C 59.27, H 5.74, N 5.10Found: C 59.27, H 5.74, N 5.10
<실시예 3><Example 3>
(S)-4-[4-[(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산-벤조산염의 합성Synthesis of (S) -4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid-benzoate
실시예 1에 따라 얻어진 (S)-4-[4-(4-클로로페닐)(2-피리딜)메톡시]피페리디노]부탄산 0.91 g(2.34 mol)을 아세트산메틸30 ㎖에 용해하고, 벤조산 0.29 g(2.37 mmol)을 첨가하여 균일하게 만든 후 감압하에 농축하였다. 잔류물에 이소프로필에테르 50 ㎖를 첨가하여 2일간 방치했더니, 시럽의 일부가 결정화되었다. 스파츌러로 뒤섞어 다시 방치했더니 전체가 결정화되었다. 이 결정을 아세트산에틸 36 ㎖로 재결정하여 목적물 0.87 g(수율:72.8 %, 광학 순도: 99.4% e.e.)을 백색 분말 결정으로서 얻었다.0.91 g (2.34 mol) of (S) -4- [4- (4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid obtained according to Example 1 was dissolved in 30 ml of methyl acetate. , Benzoic acid 0.29 g (2.37 mmol) was added to make uniform, and concentrated under reduced pressure. 50 ml of isopropyl ether was added to the residue and left for 2 days, and a part of the syrup crystallized. When mixed with spatula and left again, the whole crystallized. This crystal was recrystallized with 36 ml of ethyl acetate to obtain 0.87 g (yield: 72.8%, optical purity: 99.4% e.e.) of the target substance as white powder crystals.
[α]D 23 - 4.6°(c=1, EtOH). 융점: 136 내지 140 ℃ [α] D 23 - 4.6 ° (c = 1, EtOH). Melting Point: 136-140 ℃
이하의 실시예에서는 (R)형과 (S)형의 피페리딘 중간체의 양비(거울상 이성질체 과잉율: % e.e.)는 다음 조건에서의 고성능 액체 크로마토그래피(HPLC)로 분석하였다.In the following examples, the ratio of the (R) and (S) piperidine intermediates (enantiomer excess:% e.e.) was analyzed by high performance liquid chromatography (HPLC) under the following conditions.
칼럼: ULTORON-ES-OVM(4.6φ×150 ㎜)(Shinwa Kako K.K. 제품)Column: ULTORON-ES-OVM (4.6φ × 150 mm) (manufactured by Shinwa Kako K.K.)
이동상: 20 mM KH2PO4 수용액(pH4.6)/에탄올(실시예 4 내지 7; 100:10, 실시예 8 내지 20; 100:6)Mobile phase: 20 mM KH 2 PO 4 aqueous solution (pH4.6) / ethanol (Examples 4-7; 100: 10, Examples 8-20; 100: 6)
유량: 1.0 ㎖/분Flow rate: 1.0 ml / min
검출 파장: UV-220 nmDetection wavelength: UV-220 nm
<실시예 4><Example 4>
(1) (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 1.00 g과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산 1.27 g을, 에탄올 30 ㎖와 물 7 ㎖의 혼합액에 가열 용해하고, 서서히 냉각시킨 후 25 ℃에서 2시간 교반하였다.(1) 1.00 g of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl 1.27 g of) -3- (2-nitro-5-chlorophenylthio) propionic acid was dissolved in a mixture of 30 ml of ethanol and 7 ml of water, and gradually cooled, followed by stirring at 25 ° C for 2 hours.
석출된 결정을 여과에 의해 모으고, 에탄올로 세정한 후, 50 ℃에서 감압 건조하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산의 염의 조결정 0.97 g을 얻었다.The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure at 50 ° C. to give (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 0.97 g of a crude crystal of a salt of 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid was obtained.
[α]D 25-11.7°(c=1, 디메틸포름아미드)[α] D 25 -11.7 ° (c = 1, dimethylformamide)
94.1 % d.e.94.1% d.e.
(2) 이 조결정 0.80 g을 에탄올 20 ㎖와 물 4 ㎖의 혼합액으로 재결정하여 결정 0.71 g을 얻었다.(2) 0.80 g of this crude crystal was recrystallized from a mixed solution of 20 ml of ethanol and 4 ml of water to obtain 0.71 g of crystal.
[α]D 25-10.9°(c=1, 디메틸포름아미드)[α] D 25 -10.9 ° (c = 1, dimethylformamide)
100 % d.e.100% d.e.
(3) 이 재결정 생성물 0.35 g을 물 3 ㎖와 디메틸포름아미드 0.5 ㎖의 혼합액에 용해하고, 1 M 수산화 나트륨 수용액 0.76 ㎖를 첨가하여 분해하고, 3회 디에틸에테르로 추출하였다. 디에틸에테르층을 포화 식염수로 세정한 후, 무수 황산 나트륨으로 건조하고 디에틸에테르를 증류하여 오일상의 목적물 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 0.14 g을 얻었다.(3) 0.35 g of this recrystallized product was dissolved in a mixed solution of 3 ml of water and 0.5 ml of dimethylformamide, 0.76 ml of an aqueous 1 M sodium hydroxide solution was added to decompose, and extracted with diethyl ether three times. The diethyl ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and diethyl ether was distilled to give the desired substance as an oil (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] pi. 0.14 g of ferridine was obtained.
[α]D 25 - 21.6°(c=0.99, 에탄올) [α] D 25 - 21.6 ° (c = 0.99, ethanol)
100 % e.e.100% e.e.
<실시예 5>Example 5
(±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로페닐티오)프로피온산을 실시예 4-(1),(2) 및 (3)과 마찬가지로 처리하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 얻었다.(±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- ( 2-nitrophenylthio) propionic acid was treated in the same manner as in Examples 4- (1), (2) and (3) to give (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] pi Got ferridine.
<실시예 6><Example 6>
(1) (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 2.00 g과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산 1.52 g을, 에탄올 25 ㎖와 물 5 ㎖의 혼합액에 가열 용해하고, 50 ℃에서 소량의 종자 결정을 가한 후 25 ℃에서 2시간 교반하였다. 석출된 결정을 여과에 의해 모으고, 에탄올로 세정한 후, 50 ℃에서 감압 건조하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘과 (2R,3R)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산의 염의 조결정 1.95 g을 얻었다.(1) 2.00 g of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl 1.52 g of) -3- (2-nitro-5-chlorophenylthio) propionic acid was dissolved in a mixture of 25 ml of ethanol and 5 ml of water, and after adding a small amount of seed crystals at 50 캜, the mixture was stirred at 25 캜 for 2 hours. It was. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure at 50 ° C. to give (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, Crude crystals of 1.95 g of a salt of 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid were obtained.
[α]D 26 - 11.6°(c=1, 디메틸포름아미드) [α] D 26 - 11.6 ° (c = 1, dimethylformamide)
94.0 % d.e.94.0% d.e.
(2) 이 조결정 1.70 g을 에탄올 42 ㎖와 물 8.5 ㎖의 혼합액 중에서 재결정하여 결정 1.53 g을 얻었다.(2) 1.70 g of this crude crystal was recrystallized in a mixed solution of 42 ml of ethanol and 8.5 ml of water to obtain 1.53 g of crystal.
[α]D 25 - 11.0°(c=1, 디메틸포름아미드) [α] D 25 - 11.0 ° (c = 1, dimethylformamide)
100 % d.e.100% d.e.
(3) 이 재결정 생성물을 실시예 4-(3)과 마찬가지로 처리하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 얻었다.(3) This recrystallized product was treated in the same manner as in Example 4- (3) to obtain (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
<실시예 7><Example 7>
(1) (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 1.00 g과 (2S,3S)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로-5-클로로페닐티오)프로피온산 1.15 g을, 에탄올 10 ㎖와 물 2 ㎖의 혼합액에 가열 용해하고, 서서히 냉각시킨 후 25 ℃에서 2시간 교반하였다. 석출된 결정을 여과에 의해 모으고, 에탄올로 세정한 후, 50 ℃에서 감압 건조하여 (R)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘과 (2S,3S)-2-히드록시-3-(4-메톡시페닐)-3-(2-니트로페닐티오)프로피온산의 염의 조결정 0.84 g을 얻었다.(1) 1.00 g of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2S, 3S) -2-hydroxy-3- (4-methoxyphenyl 1.15 g of) -3- (2-nitro-5-chlorophenylthio) propionic acid was dissolved in a mixed solution of 10 ml of ethanol and 2 ml of water, cooled slowly, and stirred at 25 ° C for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure at 50 ° C. to give (R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2S, 0.84 g of a crude crystal of a salt of 3S) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitrophenylthio) propionic acid was obtained.
[α]D 25 - 40.6°(c=1, 디메틸포름아미드) [α] D 25 - 40.6 ° (c = 1, dimethylformamide)
89.8 % d.e.89.8% d.e.
(2) 이 조결정 0.70 g을 에탄올 8.4 ㎖와 물 0.9 ㎖의 혼합액 중에서 재결정하여 결정 0.61 g을 얻었다.(2) 0.70 g of this crude crystal was recrystallized in a mixed solution of 8.4 ml of ethanol and 0.9 ml of water to obtain 0.61 g of crystal.
[α]D 25 - 38.9°(c=1, 디메틸포름아미드) [α] D 25 - 38.9 ° (c = 1, dimethylformamide)
100 % d.e.100% d.e.
(3) 이 재결정 생성물 0.50 g을 실시예 4-(3)과 마찬가지로 처리하여 (R)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 0.21 g을 얻었다.(3) 0.50 g of this recrystallized product was treated in the same manner as in Example 4- (3) to obtain 0.21 g of (R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
[α]D 25+21.3°(c=1, 에탄올)[α] D 25 + 21.3 ° (c = 1, ethanol)
100 % e.e.100% e.e.
<실시예 8><Example 8>
(1) (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 10 g(33 mmol)과 N-아세틸-L-페닐알라닌 4.1 g(19.8 mmol)을 아세트산에틸 400 ㎖에 50 내지 60 ℃에서 가열 용해한 후, 약 40 ℃까지 냉각하고, (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘·N-아세틸-L-페닐알라닌염의 종자 결정을 소량 첨가하였다. 서서히 냉각시킨 후, 약 30 ℃에서 1시간 교반하고, 다시 25 ℃에서 3시간 교반하였다. 석출된 결정을 여과하고 모아서, 아세트산에틸 40 ㎖로 세정한 후, 50 내지 60 ℃에서 건조하여 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘·N-아세틸-L-페닐알라닌염의 조결정 7.14 g(수율 42.4 %)을 얻었다.(1) 10 g (33 mmol) of (±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and 4.1 g (19.8 mmol) of N-acetyl-L-phenylalanine were acetic acid After dissolving in 400 ml of ethyl by heating at 50 to 60 ° C., the mixture was cooled to about 40 ° C. and then (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidineN-acetyl- A small amount of seed crystals of L-phenylalanine salt was added. After cooling slowly, it stirred at about 30 degreeC for 1 hour, and also stirred at 25 degreeC for 3 hours. The precipitated crystals were collected by filtration, washed with 40 ml of ethyl acetate, dried at 50 to 60 ° C, and then (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine. 7.14 g (yield 42.4%) of crude crystals of N-acetyl-L-phenylalanine salt were obtained.
[α]D 23+30.2°(c=1, 메탄올)[α] D 23 + 30.2 ° (c = 1, methanol)
95.2 % d.e.95.2% d.e.
(2) 이 조결정 7.0 g을 아세트산에틸 350 ㎖에 환류하에 가열 용해하고, 서냉 후 약 30 ℃에서 1시간, 이어서 20 ℃에서 3시간 교반하였다. 석출된 결정을 여과하고, 아세트산에틸 40 ㎖로 세정한 후 50 내지 60 ℃에서 건조하여 결정 6.44 g(재결정 수율 92.0 %)을 얻었다.(2) 7.0 g of this crude crystal was dissolved in 350 ml of ethyl acetate under reflux, and the mixture was stirred at about 30 ° C for 1 hour and then at 20 ° C for 3 hours after slow cooling. Precipitated crystals were filtered, washed with 40 ml of ethyl acetate, and dried at 50 to 60 ° C., yielding 6.44 g of crystals (yield 92.0%).
[α]D 23+29.6°(c=1, 메탄올)[α] D 23 + 29.6 ° (c = 1, methanol)
98.9 % d.e.98.9% d.e.
(3) 이 재결정 생성물 6.0 g(11.7 mmol)을 물 30 ㎖에 용해하고, 2 M 염산 12.9 ㎖를 첨가하고, 아세트산에틸 20 ㎖로 3회 추출하여 N-아세틸-L-페닐알라닌을 회수하였다. 그 수용액 층에 5 M 수산화 나트륨 수용액 10.3 ㎖를 첨가하고, 아세트산에틸 20 ㎖로 3회 추출하고, 포화 식염수로 세정한 후, 무수 황산 마그네슘으로 건조하였다. 용매를 제거하여 목적하는 오일상의 (S)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 3.45 g(수율 96.9 %)을 얻었다.(3) 6.0 g (11.7 mmol) of this recrystallized product was dissolved in 30 ml of water, 12.9 ml of 2M hydrochloric acid was added, and extracted three times with 20 ml of ethyl acetate to recover N-acetyl-L-phenylalanine. 10.3 ml of 5 M aqueous sodium hydroxide solution was added to the aqueous solution layer, extracted three times with 20 ml of ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 3.45 g (yield 96.9%) of (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine as the desired oil.
[α]D 25 - 21.4°(c=1, 에탄올) [α] D 25 - 21.4 ° (c = 1, ethanol)
99.0 % e.e.99.0% e.e.
회수된 N-아세틸-L-페닐알라닌은 2.15 g(수율 88.2 %)이며, [α]D 25는 +40.3° (c=1, 메탄올)이었다.The recovered N-acetyl-L-phenylalanine was 2.15 g (yield 88.2%) and [α] D 25 was + 40.3 ° (c = 1, methanol).
(4) (1)에서 얻어진 광학 분할 모액을 농축하고, 잔류물에 2 M 염산 20.9 ㎖을 첨가하고, 아세트산에틸 20 ㎖로 3회 추출하여 N-아세틸-L-페닐알라닌을 회수하였다. 그 수용액 층에 5 M 수산화 나트륨 수용액 16.7 ㎖를 첨가하고, 아세트산에틸 20 ㎖로 3회 추출하여 포화 식염수로 세정한 후, 무수 황산 마그네슘으로 건조하였다. 용매를 제거하여 광학 순도 63.9 % e.e.의 (R)형 이성질체가 과잉인 4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘 6 g을 얻었다. 또한, 회수된 N-아세틸-L-페닐알라닌 1.02 g이 얻어지고, [α]D 25는 +40.3°(c=1, 메탄올)이었다.(4) The optically divided mother liquid obtained in (1) was concentrated, 20.9 ml of 2M hydrochloric acid was added to the residue, and extracted three times with 20 ml of ethyl acetate to recover N-acetyl-L-phenylalanine. 16.7 ml of 5 M sodium hydroxide aqueous solution was added to the aqueous solution layer, extracted three times with 20 ml of ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 6 g of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine with an excess of the (R) type isomer of 63.9% ee of optical purity. Also, 1.02 g of recovered N-acetyl-L-phenylalanine was obtained, and [α] D 25 was + 40.3 ° (c = 1, methanol).
<실시예 9 내지 20><Examples 9 to 20>
실시예 8-(1)의 방법에 준하여 표 5에 나타내는 광학 분할제 및 용매를 사용하여 (±)-4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘을 광학 분할하였다. 얻어진 각각의 부분 입체 이성질체 염을 상기의 HPLC 조건으로 분석한 결과를 표 5에 나타냈다.(±) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine was optically prepared using the optical dividing agent and solvent shown in Table 5 according to the method of Example 8- (1). Divided. Table 5 shows the results of analyzing each of the obtained diastereomeric salts under the above HPLC conditions.
<실시예 21>Example 21
상기 실시예 4 내지 20에서 얻어진 광학 활성 피페리딘 중간체를 사용하여 참고예 3 및 실시예 1에 따라 얻어진 각각의 부탄산을 실시예 2 또는 실시예 3에 따라 처리하여 부탄산-벤젠술폰산염 또는 부탄산-벤조산염을 얻었다. 얻어진 부탄산-벤젠술폰산염 또는 부탄산-벤조산염은 실시예 2 또는 실시예 3에서 얻어진 부탄산-벤젠술폰산염 또는 부탄산-벤조산염과 동일한 물성을 나타냈다.Each butanoic acid obtained according to Reference Example 3 and Example 1 using the optically active piperidine intermediate obtained in Examples 4 to 20 was treated according to Example 2 or Example 3 to give butanic acid-benzenesulfonate or Butanoic acid-benzoate was obtained. The obtained butanoic acid-benzenesulfonate or butanoic acid-benzoate showed the same physical properties as the butanoic acid-benzenesulfonate or butanoic acid-benzoate obtained in Example 2 or Example 3.
또한 실시예 중, 부분 입체 이성질체 염의 「d.e.」는 염에 포함되는 4-[(4-클로로페닐)(2-피리딜)메톡시]피페리딘의 e.e.를 말한다.In addition, in an Example, "d.e." of a diastereomeric salt refers to e.e. of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine contained in the salt.
Claims (7)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34785396A JP3157118B2 (en) | 1996-12-26 | 1996-12-26 | Optical resolution method of piperidine derivative using acylamino acid |
| JP96-347853 | 1996-12-26 | ||
| JP34785196A JP3157117B2 (en) | 1996-12-26 | 1996-12-26 | Optical resolution method of piperidine derivative |
| JP34789596 | 1996-12-26 | ||
| JP96-347851 | 1996-12-26 | ||
| JP96-347895 | 1996-12-26 | ||
| PCT/JP1997/004826 WO1998029409A1 (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compound and process for producing the same |
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| Publication Number | Publication Date |
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| KR20000062337A KR20000062337A (en) | 2000-10-25 |
| KR100515227B1 true KR100515227B1 (en) | 2005-09-16 |
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| KR10-1999-7005802A KR100515227B1 (en) | 1996-12-26 | 1997-12-25 | Acid-Addition Salts of Optically Active Piperidine Compound and Process for Producing the Same |
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| EP (1) | EP0949260B1 (en) |
| KR (1) | KR100515227B1 (en) |
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| AT (1) | ATE217872T1 (en) |
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| CA (1) | CA2275987C (en) |
| DE (1) | DE69712784T2 (en) |
| DK (1) | DK0949260T3 (en) |
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| MY (1) | MY118016A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101132949B1 (en) * | 2009-09-08 | 2012-04-10 | 경희대학교 산학협력단 | Bepotastine salicylate, preparation method thereof and antihistamine or antialergy pharmaceutical composition containing the same as an active ingredient |
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| Publication number | Publication date |
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| US6780877B2 (en) | 2004-08-24 |
| US7282589B2 (en) | 2007-10-16 |
| HK1022477A1 (en) | 2000-08-11 |
| DE69712784T2 (en) | 2002-11-21 |
| EP0949260A1 (en) | 1999-10-13 |
| EP0949260B1 (en) | 2002-05-22 |
| KR20000062337A (en) | 2000-10-25 |
| CN1242013A (en) | 2000-01-19 |
| CN1098262C (en) | 2003-01-08 |
| CN1231478C (en) | 2005-12-14 |
| US20020026054A1 (en) | 2002-02-28 |
| US6307052B1 (en) | 2001-10-23 |
| ES2173499T3 (en) | 2002-10-16 |
| MY118016A (en) | 2004-08-30 |
| PT949260E (en) | 2002-09-30 |
| WO1998029409A1 (en) | 1998-07-09 |
| DK0949260T3 (en) | 2002-09-09 |
| ID21985A (en) | 1999-08-19 |
| AU7890698A (en) | 1998-07-31 |
| ATE217872T1 (en) | 2002-06-15 |
| CA2275987A1 (en) | 1998-07-09 |
| DE69712784D1 (en) | 2002-06-27 |
| CA2275987C (en) | 2006-12-19 |
| CN1446812A (en) | 2003-10-08 |
| TW486475B (en) | 2002-05-11 |
| US20040220226A1 (en) | 2004-11-04 |
| EP0949260A4 (en) | 2000-03-15 |
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